Faculty Bibliography

Infant cries evoke powerful responses in parents^1-4. Whether parental animals are intrinsically sensitive to neonatal vocalizations, or instead learn about vocal cues for parenting responses is unclear. In mice, pup-naive virgin females do not recognize the meaning of pup distress calls, but retrieve isolated pups to the nest after having been co-housed with a mother and litter^5-9. Distress calls are variable, and require co-caring virgin mice to generalize across calls for reliable retrieval^10,11. Here we show that the onset of maternal behaviour in mice results from interactions between intrinsic mechanisms and experience-dependent plasticity in the auditory cortex. In maternal females, calls with inter-syllable intervals (ISIs) from 75 to 375 milliseconds elicited pup retrieval, and cortical responses were generalized across these ISIs. By contrast, naive virgins were neuronally and behaviourally sensitized to the most common ('prototypical') ISIs. Inhibitory and excitatory neural responses were initially mismatched in the cortex of naive mice, with untuned inhibition and overly narrow excitation. During co-housing experiments, excitatory responses broadened to represent a wider range of ISIs, whereas inhibitory tuning sharpened to form a perceptual boundary. We presented synthetic calls during co-housing and observed that neurobehavioural responses adjusted to match these statistics, a process that required cortical activity and the hypothalamic oxytocin system. Neuroplastic mechanisms therefore build on an intrinsic sensitivity in the mouse auditory cortex, and enable rapid plasticity for reliable parenting behaviour.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Advances in cancer treatment have increased survival for many patients, prompting a need for greater recognition of the long-term complications of treatment. Chemotherapy agents have the potential to induce carcinogenesis and can increase the risk of secondary malignancy. Pegylated liposomal doxorubicin (PLD) used for maintenance treatment of recurrent high-grade serous cancers has been associated with the development of oral cavity squamous cell carcinoma (SCC). STUDY DESIGN/METHODS:Retrospective review. METHODS:Cases of oral cavity SCC in patients with recurrent high-grade serous cancer treated with PLD between 1997 and 2017 at a single institution were reviewed. RESULTS:). Seven patients tested positive for BRCA mutations (four BRCA 1+, three BRCA 2+). No patients had a history of alcohol or tobacco use. All had early-stage oral cavity disease; five were T1N0, two were T2N0, and one had carcinoma in situ. All patients underwent surgery, and two received adjuvant radiation. Four developed locoregional recurrence requiring additional treatment. Of these, one patient died from complications of oral SCC, one developed recurrent ovarian cancer, and two had no evidence of disease of the oral cavity or ovarian cancer at the last follow-up. CONCLUSIONS:Long-term PLD therapy may be associated with the development of oral cavity SCC. A high index of suspicion and routine head and neck examination should be included in follow-up for exposed patients. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 2019.

OBJECTIVE:To investigate and improve compliance of thyroid function monitoring in head and neck cancer patients who received radiotherapy to the cervical region before and after instituting quality improvement interventions. METHODS:Using the Plan, Do, Study, Act (PDSA) methodology, patients with head and neck malignancies who received radiotherapy to the cervical region from 2013-2015 were identified at a tertiary medical center. The status of the patients' thyroid monitoring and related characteristics were recorded. A quality improvement project was subsequently implemented by data sharing and providing feedback to practitioners involved in head and neck cancer care and creating a tracking database for all patients who received radiotherapy to the neck. After implementation of these interventions, data was collected on patients meeting the inclusion criteria from 2015-2017. RESULTS:One hundred fifty-six patients met criteria pre-intervention and ninety-eight patients met criteria post-intervention. Compliance of thyroid monitoring went up from 34% to 80% after interventions (P < .0001). There was a significant increase in thyroid testing performed by radiation oncologists after interventions from 2% to 21%, while medical oncologists and otolaryngologists remained consistent in their compliance rates. CONCLUSION/CONCLUSIONS:It is possible to improve compliance with evidence-based recommendations and improve the quality-of-care for head and neck cancer survivors through simple, cost effective interventions. LEVEL OF EVIDENCE/METHODS:2 Laryngoscope, 2019.

PURPOSE:Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA. PATIENTS AND METHODS:E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections. RESULTS:120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients. CONCLUSIONS:We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.

PURPOSE/OBJECTIVE:To describe the surgical technique and outcome in a series of patients who underwent revision cochlear implantation using a double array or split electrode device. All patients developed ossified cochleae due to meningitis and were functioning poorly with the previous implant. METHODS:Four patients between the ages of 4-15 years underwent revision with five double-array cochlear implant devices. One patient underwent bilateral revision surgery. All patients had previous meningitis with CT and MRI imaging studies that demonstrated completely ossified cochleae. The time interval range between the disease and the initial cochlear implantation and was 4 months to 3 years. The patient's data were retrospectively analyzed with emphasis on the surgical technique, the number of electrodes inserted, and the number of active electrodes at follow-up. In addition, pre and post-revision surgery function was compared. RESULTS:The revision surgery was carried out 2-11 years after the initial surgery. Two tunnels, basal and apical, were drilled in the ossified cochlea. In each of the tunnels, 5 to 11 electrodes were inserted. While the number of active electrodes before revision was 0-5, after revision with the double array, it was increased to 8-12, resulting in improved auditory and speech function. CONCLUSION/CONCLUSIONS:Revision cochlear implantation with a double array implant using the two tunnel technique can increase the number of active electrodes. This leads to a better outcome in post-meningitis children with completely ossified cochleae and a poor functioning previous device.

Sequential activation of neurons has been observed during various behavioral and cognitive processes, but the underlying circuit mechanisms remain poorly understood. Here, we investigate premotor sequences in HVC (proper name) of the adult zebra finch forebrain that are central to the performance of the temporally precise courtship song. We use high-density silicon probes to measure song-related population activity, and we compare these observations with predictions from a range of network models. Our results support a circuit architecture in which heterogeneous delays between sequentially active neurons shape the spatiotemporal patterns of HVC premotor neuron activity. We gauge the impact of several delay sources, and we find the primary contributor to be slow conduction through axonal collaterals within HVC, which typically adds between 1 and 7.5 ms for each link within the sequence. Thus, local axonal "delay lines" can play an important role in determining the dynamical repertoire of neural circuits.

STUDY OBJECTIVES/OBJECTIVE:The effectiveness of hypoglossal nerve stimulation (HGNS) in the treatment of obstructive sleep apnea (OSA) depends upon the selective stimulation of nerve fibers that innervate tongue muscles that produce tongue protrusion (genioglossus) and stiffening (transverse/vertical), while avoiding fibers that innervate muscles that produce tongue retraction (styloglossus/hyoglossus). Post-operative treatment failures can be related to mixed activation of retractor and protrusor muscles despite intraoperative efforts to identify and avoid nerve fibers that innervate retractor muscles. This study describes a novel intraoperative protocol that more optimally identifies mixed activation by utilizing an expanded set of stimulation/recording parameters. METHODS:Case series in a university hospital setting of patients undergoing unilateral HGNS implantation for OSA. Data included EMG responses in genioglossus and styloglossus/hyoglossus to intraoperative stimulation with an implantable pulse generator (IPG) using unipolar (---, o-o) and bipolar (+-+) settings. RESULTS:In a subset of patients (3/55), low-intensity unipolar IPG stimulation revealed significant mixed activation of styloglossus/hyoglossus and genioglossus muscles that was not evident under standard bipolar IPG stimulation conditions. Additional surgical dissection and repositioning of the electrode stimulation cuff reduced mixed activation. CONCLUSIONS:A novel intraoperative neurophysiological monitoring protocol was able to detect significant mixed activation during HGNS that was otherwise absent with standard parameters. This enabled successful electrode cuff repositioning and dramatic reduction of mixed activation.

IMPORTANCE/OBJECTIVE:Foreign body (FB) aspiration into the airway is a significant cause of pediatric morbidity and mortality, yet the clinical presentation is diverse and dynamic. There are conflicting recommendations which pre-procedural findings support performing a bronchoscopy, the gold standard for diagnosis and removal of FBs, however a procedure that entails general anesthesia and possible risks. OBJECTIVE:Decision whether to proceed to a bronchoscopy may be challenging. Our goal was to enhance decision-making by analyzing the diagnostic values of the different pre-procedural findings in this setting. DATA SOURCES/METHODS:A comprehensive search was performed in PUBMED, EMBASE and Cochrane Review databases to find studies from the last 19 years that reported pre-procedural history, physical examination and radiological findings in patients who had bronchoscopies. STUDY SELECTION/METHODS:Studies were included of pediatric populations if they contained bronchoscopy results (positive and negative for foreign body) with a breakdown according to pre-intervention findings. DATA EXTRACTION AND SYNTHESIS/METHODS:Titles and abstracts retrieved from our search were screened. Thereafter, full-texts were carefully reviewed and selected for inclusion if the aforementioned criteria were met. PRISMA guidelines for systematic review and meta-analyses were followed. MAIN OUTCOME(S) AND MEASURE(S)/UNASSIGNED:Cumulative weighted prevalence, sensitivity, specificity, positive and negative predictive values of each pre-procedural finding were calculated, as well as for the "classic triad" (history of an acute event, wheezing, and unilateral decreased breath sounds). Calculation for other combinations of findings, or optimally, constructing a weighted score based on all the findings for each specific patient were not possible to perform, as the specific data breakdown is rarely reported. RESULTS:Fifteen studies met inclusion criteria, totaling 5606 patients who underwent bronchoscopies. All studies but one were single center based and all except one were retrospective. No single finding has both positive and negative predictive values over 50%. The "classic triad" has 90% specificity, however only 35% sensitivity. CONCLUSIONS:The data is very heterogeneous with regard to pre-procedural findings and how best to guide treatment according to them. This meta-analysis provides cumulative weighted metrics for each finding, to optimize decision-making for the individual patient. Future reporting of data should be enhanced, so that combinations of findings for a specific patient can be used to optimize management. LEVEL OF EVIDENCE/METHODS:4.

Oral cancer patients often have severe, chronic, and mechanically induced pain at the site of the primary cancer. Oral cancer pain is initiated and maintained in the cancer microenvironment and attributed to release of mediators that sensitize primary sensory nerves. This study was designed to investigate the histopathology associated with painful oral cancers in a preclinical model. The relationship of pain scores with pathologic variables was also investigated in a cohort of 72 oral cancer patients. Wild-type mice were exposed to the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Nociceptive (pain) behavior was measured with the dolognawmeter, an operant device and assay for measuring functional and mechanical allodynia. Lesions developed on the tongues and esophagi of the 4NQO-treated animals and included hyperkeratoses, papillomas, dysplasias, and cancers. Papillomas included lesions with benign and dysplastic pathological features. Two histologic subtypes of squamous cell carcinomas (SCCs) were identified-SCCs with exophytic and invasive components associated with papillary lesions (pSCCs) and invasive SCCs without exophytic histology (iSCCs). Only the pSCC subtype of tongue cancer was associated with nociceptive behavior. Increased tumor size was associated with greater nociceptive behavior in the mouse model and more pain experienced by oral cancer patients. In addition, depth of invasion was associated with patient-reported pain. The pSCC histology identifies 4NQO-induced tongue cancers that are expected to be enriched for expression and release of nociceptive mediators.